Neuro Innovations - Tracking the True Culprit Behind ALS

Collaborations in Discovery

Tracking the True Culprit Behind ALS

Date: November 1, 2011

Jeffrey Rothstein

Researchers have long believed they know what causes the devastating, little treatable and ultimately fatal damage to the brains of patients with amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease. Namely, astrocytes—cells that support neurons in several ways—lose their ability to sweep away glutamate, a molecule that is used by the brain to transmit signals between neurons. The neurons end up swimming in glutamate, which in high concentrations damages them.

But neurologist Jeffrey Rothstein wondered if that was really the main problem. Rothstein, who heads the Brain Science Institute and the Johns Hopkins Center for ALS Research, figured that if the astrocyte—glutamate transport mechanism goes awry in ALS, something else must be off too. After all, the countless chemical pathways in the body act together as a network, rarely working or malfunctioning entirely in isolation. And sure enough, he and colleagues found there was a mechanism that had been overlooked.

Neurons get energy from glucose provided by astrocytes. But they also get some energy from lactate, and the lactate, Rothstein’s team discovered, turns out to come not from astrocytes but from oligodendroglia, the cells that help make and maintain the fatty sheaths around nerve cells. This lactate-delivery process is much more important to the proper functioning of neurons than realized—and it breaks down in brains afflicted with ALS. “The literature was wrong,” says Rothstein. “We all thought ALS was solely a disease of astrocytes. But we really need to focus on what’s happening in the oligodendroglia.”

Rothstein and his colleagues have already looked at ways to try to restore the oligodendroglial lactate-production mechanism that’s broken in ALS, and in mice some early efforts have already shown promise in halting the progress of the disease. What’s more, Rothstein has collaborated with imaging researchers in working on an oligodendroglia-spotting technique that could provide a means for diagnosing and tracking ALS from its earliest stages. “We’ve never had a biomarker for ALS, and that’s been a big obstacle,” says Rothstein, who notes that the technique is now being tested in patients. “We now have an entirely new way of tackling ALS, and it’s come right out of left field.”

Challenge: Find a treatment for the fatal brain disorder ALS, and a means for early diagnosis

Approach: Shift research focus from white matter glial cells to gray matter, where the problems may really lie

Progress: New future drug target from mouse studies, and a new imaging technique for diagnosis is being tested in patients